title: Degradome products of the matricellular protein CCN1 as modulators of pathological angiogenesis in the retina.
abstract: CCN1 is a matricellular protein involved in normal vascular development and tissue repair. CCN1 exhibits cell- and context-dependent activities that are reflective of its tetramodular structure phylogenetically linked to four domains found in various matrix proteins. Here, we show that vitreal fluids from patients with proliferative diabetic retinopathy (PDR) were enriched with a two-module form of CCN1 comprising completely or partially the insulin-like growth factor-binding protein (IGFBP) and von Willebrand factor type C (vWC) domains. The two- and three-module forms comprising, in addition to IGFBP and vWC, the thrombospondin type 1 (TSP1) repeats are CCN1 degradome products by matrix metalloproteinase-2 and -14. The functional significance of CCN1 and its truncated variants was determined in the mouse model of oxygen-induced retinopathy, which simulates neovascular growth associated with PDR and assesses treatment outcomes. In this model, lentivirus-mediated expression of either CCN1 or the IGFBP-vWC-TSP1 form reduced ischemia-induced neovascularization, whereas ectopic expression of the IGFBP-vWC variant exacerbated pathological angiogenesis. The IGFBP-vWC form has potent proangiogenic properties promoting retinal endothelial cell growth, migration, and three-dimensional tubular structure formation, whereas the IGFBP-vWC-TSP1 variant suppressed cell growth and angiogenic gene expression. Both IGFBP-vWC and IGFBP-vWC-TSP1 forms exhibited predictable variations of their domain folding that enhanced their functional potential. These data provide new insights into the formation and activities of CCN1-truncated variants and raise the predictive value of the form containing completely or partially the IGFBP and vWC domains as a surrogate marker of CCN1 activity in PDR distinguishing pathological from physiological angiogenesis.
authors.affiliation: Department of Cell Biology, State University of New York Eye Institute, Downstate Medical Center, Brooklyn, New York 11203, USA.
authors.forename: Jinok
authors.initials: J
authors.lastname: Choi
authors.forename: Ann
authors.initials: A
authors.lastname: Lin
authors.forename: Eric
authors.initials: E
authors.lastname: Shrier
authors.forename: Lester F
authors.initials: LF
authors.lastname: Lau
authors.forename: Maria B
authors.initials: MB
authors.lastname: Grant
authors.forename: Brahim
authors.initials: B
authors.lastname: Chaqour
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D055515:Cysteine-Rich Protein 61 / Q000235:genetics / Q000378:metabolism*; D003930:Diabetic Retinopathy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D051381:Rats; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism; D014841:von Willebrand Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; C501848:CCN1 protein, human; C491850:CCN1 protein, mouse; C501849:CCN1 protein, rat; D055515:Cysteine-Rich Protein 61; D018969:Insulin-Like Growth Factor Binding Proteins; D019700:Thrombospondin 1; C582391:Thbs1 protein, rat; D014841:von Willebrand Factor
keywords: Angiogenesis; Cysteine-rich Protein 61 (CCN1); Endothelial Cell; Extracellular Matrix Proteins; Ischemia; Matricellular Protein; Matrix Metalloproteinase (MMP); Protein Degradation; Protein Domains; Retina